The present invention relates essentially to a non-therapeutical process for deterring vermin, which is based on the usage of the largely known compounds of formula (I) shown below. Furthermore, it relates to corresponding vermin-repelling compositions which contain these substances as the active ingredient, to compounds of formula (I) for the preparation of vermin-deterring compositions, and to the use of compounds of formula (I) in the defence against vermin.
It has surprisingly been found that the compounds of formula (I) below 
or their acid addition salts, wherein
R is hydrogen, C1-C20-alkyl or xe2x80x94C(O)xe2x80x94R8, whereby R8 is C1-C20-alkyl, C1-C20-alkoxy, unsubstituted phenyl or phenyl which is substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, cyano, hydroxyl, alkoxy, amino or nitro;
R1 is hydrogen, C1-C20-alkyl, xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(S)xe2x80x94R4, C(O)xe2x80x94Oxe2x80x94R5, xe2x80x94C(O)xe2x80x94NHxe2x80x94R6 or xe2x80x94C(S)xe2x80x94NHxe2x80x94R7; whereby R3, R4, R5, R6 and R7, independently of one another, signify C1-C10-alkyl, acetoxy, C1-C10-haloalkyl, C1-C10-alkoxy or C1-C10-haloalkoxy, or independently of one another, denote unsubstituted phenyl or phenyl which is substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, cyano, hydroxyl, C1-C3-alkoxy, amino, CHO or nitro;
R2 and R3, independently of one another, are hydrogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, cyano, hydroxyl, amino, aryl or nitro; p1 Ra denotes hydrogen, unsubstituted C1-C20-alkyl or C1-C20-alkyl which is substituted once or many times by halogen, cyano, hydroxyl, alkoxy, nitro, phenyl, biphenyl, benzyloxy or phenoxyphenyl, whereby each phenyl, biphenyl, benzyloxy or phenoxyphenyl in turn is unsubstituted or substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, C1-C3-alkoxy, halogen, cyano, hydroxyl, amino or nitro; or it denotes C3-C8-cycloalkyl, phenyl, biphenyl, phenoxyphenyl or heterocyclyl, whereby each of these cyclic radicals is unsubstituted or substituted once or many times by C1-C3-alkyl, C2-C6-alkenyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, C1-C3-alkoxy, halogen, cyano, hydroxyl, amino, (C1-C3alkyl)2N, acetyl or nitro; or it denotes C1-C6-alkylene-aryl , whereby the aryl radical is unsubstituted or substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, cyano, hydroxyl or nitro; or it denotes C1-C20-alkyl which, depending on the number of carbon atoms, is interrupted by oxygen at one or several positions; and Rb signifies hydrogen, C1-C20-alkyl, heterocyclyl or aryl, whereby each of the cyclic radicals is unsubstituted or substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, C2-C6-alkenyl, halogen, cyano, hydroxyl, C1-C3-alkoxy, amino, (C1-C3-alkyl)2N, or nitro;
are eminently suitable for deterring vermin. Through the usage according to the invention of the above compounds, the most varied vermin of humans, animals, objects or certain places can be deterred, whereby numerous compounds within the scope of formula (I) are notable for their particularly long duration of efficacy.
Compounds of formula (I) having at least one basic centre may form e.g. acid addition salts. These are formed for example with strong inorganic acids, such as mineral acids, e.g. perchloric acid, sulphuric acid, nitric acid, nitrous acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, typically C1-C4alkanecarboxylic acids substituted where appropriate for example by halogen, e.g. acetic acid, such as dicarboxylic acids that are unsaturated where appropriate, e.g. oxalic, malonic, succinic, maleic, fumaric or phthalic acid, typically hydroxycarboxylic acids, e.g. ascorbic, lactic, malic, tartaric or citric acid, or benzoic acid, or with organic sulphonic acids, typically C1-C4alkanesulphonic or arylsulphonic acids substituted where appropriate for example by halogen, e.g. methanesulphonic or p-toluenesulphonic acid. Of the salts, particular preference is given to those formed with strong acids, especially with mineral acids, in particular with the hydrohalic acids HCl and HBr.
All multiple substitutions are to be interpreted such that identical or different substituents may occur simultaneously.
The alkyl groups present in the definitions of the substituents may be straight-chained or branched, depending on the number of carbon atoms, and they may be for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl, as well as the branched isomers thereof, for example isopropyl, isobutyl, sec.-butyl, tert.-butyl, isopentyl, neopentyl or isohexyl. Alkoxy, haloalkyl and haloalkoxy radicals are derived from the said alkyl groups.
Halo denotes halogen and normally signifies fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially chlorine, whereby the corresponding substituent may contain one or more identical or different halogen atoms.
Halogen-substituted carbon-containing groups, such as haloalkyl or haloalkoxy, may be partially halogenated or perhalogenated, whereby in the case of multiple halogenation, the halogen substituents may be identical or different. Examples of haloalkylxe2x80x94as a group per se and as structural element of other groups and compounds such as haloalkoxyxe2x80x94are methyl which is mono- to trisubstituted by fluorine, chlorine and/or bromine, such as CHF2 or CF3; ethyl which is mono- to pentasubstituted by fluorine, chlorine and/or bromine, such as CH2CF3, CF2CF3, CF2CCl3, CF2CHCl2, CF2CHF2, CF2CFCl2, CF2CHBr2, CFCHClF, CF2CHBrF or CClFCHClF; propyl or isopropyl, mono- to heptasubstituted by fluorine, chlorine and/or bromine, such as CH2CHBrCH2Br, CF2CHFCF3, CH2CF2CF3 or CH(CF3)2; and butyl or one of its isomers, mono- to nonasubstituted by fluorine, chlorine and/or bromine, such as CF(CF3)CHFCF3 or CH2(CF2)2CF3.
Alkenylxe2x80x94as a group per se and as structural element of other groups and compounds such as alkeneoxy, halogenalkenyl or halogenalkeneoxyxe2x80x94is, in each case with due consideration of the specific number of carbon atoms in the group or compound in question, either straight-chained, for example vinyl, 1-methylvinyl, allyl, 1-butenyl or 2-hexenyl, or branched, for example isopropenyl.
Appropriate cycloalkyl substituents contain 3 to 8 carbon atoms and are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Corresponding cycloalkenyl substituents may be mono- or also repeatedly unsaturated, for example cyclopentadienyl or cyclooctatetraenyl. Cyclopentyl and cyclohexyl are preferred.
In the context of the present invention, aryl is understood to be phenyl or naphthyl, especially phenyl. These aryl groups are either unsubstituted or are substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, halogen, cyano, hydroxyl, amino or nitro, whereby each multiple substitution is not limited to identical substituents; instead, mixed substituents may appear.
In the context of the present invention, heterocyclyl is understood to mean aliphatic or aromatic and additionally also benzo-condensed cyclic radicals, which contain at least one oxygen, sulphur or nitrogen atom. Five- and six-membered heterocycles are preferred. Heterocyclyl typically includes substituents such as dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrryl, furyl, thienyl, imidazolyl, tetrahydrofuryl, tetrahydropyrryl, tetrahydropyranyl, dihydrofuryl, dihydropyranyl, benzofuryl, benzothienyl, isoxazolyl, oxazolyl, thiazolyl, oxazolinyl, oxazolidinyl, indolyl, imidazolinyl, imidazolidinyl and dioxanyl. Preference is given especially to those which are unsubstituted or have one or two halogen atoms, halogen in this case denoting fluorine, chlorine or bromine, but especially chlorine. Of these heterocyclyl radicals, pyrrolidinyl, piperidinyl, pyridyl, pyrryl, furyl, thienyl, tetrahydrofuryl, benzofuryl and benzothienyl are especially notable.
A preferred sub-group in the context of formula (I) is formed by compounds wherein
R is hydrogen or C1-C6alkyl;
R1 is hydrogen, C1-C6-alkyl, xe2x80x94C(O)xe2x80x94R3 or xe2x80x94C(S)xe2x80x94R4; whereby R3 and R4 independently of one another, are C1-C3-alkyl, acetoxy, C1-C3-haloalkyl, or independently of one another, are unsubstituted phenyl or phenyl which is substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl or halogen;
R2 and R3 independently of one another, are hydrogen or C1-C3-alkyl;
Ra is hydrogen, C5-C20-alkyl, C3-C8-cycloalkyl or phenyl, whereby each of the cyclic radicals is unsubstituted or is substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, halogen, amino, (C1-C3-alkyl)2N, or acetyl; and
Rb is hydrogen, unsubstituted phenyl or phenyl which is substituted once or many times by C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, halogen, amino or (C1-C3-alkyl)2N; including the acid addition salts thereof.
In the context of formula (I), the compounds which are especially preferred are those wherein R is hydrogen and the remaining substituents are defined as under formula (I), as well as the acid addition salts thereof. A further sub-group, which is preferred because of its marked activity, is formed by compounds of formula I, wherein R1is xe2x80x94C(O)xe2x80x94R3, whereby R3 represents unsubstituted phenyl or phenyl which is substituted once or many times by C1-C3-alkyl, especially by methyl, ethyl or isopropyl, and the remaining substituents are defined as under formula (I), as well as the acid addition salts thereof. Also of interest are the compounds of formula (I), wherein R2 and R3 independently of one another, are hydrogen or methyl, and the remaining substituents are defined as under formula (I), as well as the acid addition salts thereof. Of the above-mentioned compounds of formula (I), particular preference is given to those in which Ra is C5-C20-alkyl, unsubstituted phenyl or phenyl which is substituted once or many times by C1-C3-alkyl, methoxy or chlorine; including the acid addition salts thereof, and in particular representatives in which Ra is a straight-chained C7-C20-alkyl; including the acid addition salts thereof. The free active ingredients are clearly preferred over the acid addition salts.
Each representative of the group of individual substances listed below is especially preferred owing to its marked activity, those marked with the asterix being new and representing a constituent of the present invention:2-[n-(1-hydroxyhexyl)]pyrrolidine*, 2-[n-(1-hydroxyheptyl)]pyrrolidine*, 2-[n-(1-hydroxyheptyl)]-5-(tert.-butyl)pyrrolidine, 2-[n-(1-hydroxyheptyl)]-5-(n-butyl)pyrrolidine, 2-[n-(1-hydroxyoctyl)]pyrrolidine*, [n-(1-hydroxyoctyl)]-5-(n-propyl)-pyrrolidine, 2-[n-(1-hydroxynonyl)]pyrrolidine*, 2-[n-(1-hydroxydecyl)]pyrrolidine*, 2-[n-(1-hydroxyundecyl)]pyrrolidine*, 2-[n-(1-hydroxydodecyl)]pyrrolidine*, 2-[n-(1-hydroxytridecyl)]pyrrolidine*, 2-[n-(1-hydroxytetradecyl)]pyrrolidine*, 2-[n-(1-hydroxypentadecyl)]pyrrolidine*, 2-[n-(1-hydroxyhexadecyl)]pyrrolidine*, 2-[n-(1-hydroxyheptadecyl)]-pyrrolidine*, 2-[n-(1-hydroxyoctadecyl)]pyrrolidine*, 2-[n-(1-hydroxynonadecyl)]pyrrolidine*, 2-[n-(1-hydroxyeicosyl)]pyrrolidine*, 2-[n-(1-hydroxyeneicosyl)]pyrrolidine*, 2-[(1-phenyl)(1-hydroxy)methyl]pyrrolidine, 2-[(1-[4-chorophenyl])(1-hydroxy)methyl]pyrrolidine, 2-[(1-[2,4-dimethylphenyl])(1-hydroxy)methyl]-5,5-dimethyl-pyrrolidine or 2-[(1-[3-chlorophenyl])(1-hydroxy)methyl]-5,5-dimethyl-pyrrolidine.
EP-0,281,908 discloses the use of certain xcex1,xcfx89-aminoalcohol derivatives, e.g. some piperidines as insect and tick repellents. U.S. Pat. No. 4,299,840 discloses a process for repelling ticks and other biting insects comprising the topical administration of certain pyrrolidone derivatives to animals or humans. EP-0,238,319 discloses a group pyrrolidine derivatives as inhibitors for proline-specific endopeptidase but does not report on any repellent activity.
In the context of the present invention, vermin are understood to be in particular insects, mites and ticks. These include insects of the order: Lepidoptera, Coleoptera, Homoptera, Heteroptera, Diptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and Hymenoptera. However, the vermin which may be mentioned in particular are those which trouble humans or animals and carry pathogens, for example flies such as Musca domestica, Musca vetustissima, Musca autumnalis, Fannia canicularis, Sarcophaga camaria, Lucilia cuprina, Hypoderma bovis, Hypoderma lineatum, Chrysomyia chloropyga, Dermatobia hominis, Cochliomyia hominivorax, Gasterophilus intestinalis, Oestrus ovis, Stomoxys calcitrans, Haematobia irritans and midges (Nematocera), such as Culicidae, Simulmiidae, Psychodidae, but also blood-sucking vermin, for example fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), Xenopsylla cheopis, Pulex irritans, Dermatophilus penetrans, lice, such as Damalina ovis, Pediculus humanis, biting flies and horse-flies (Tabanidae), Haematopota spp. such as Haematopota pluvialis, Tabanidea spp. such as Tabanus nigrovittatus, Chrysopsinae spp. such as Chrysops caecutiens, tsetse flies, such as species of Glossinia, biting insects, particularly cockroaches, such as Blatella germanica, Blatta orientalis, Periplaneta americana, mites, such as Dermanyssus gallinae, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp. and last but not least ticks. The latter belong to the order Acarina. Known representatives of ticks are, for example, Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros and the like, which preferably infest warm-blooded animals including farm animals, such as cattle, pigs, sheep and goats, poultry such as chickens, turkeys and geese, fur-bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as domestic animals such as cats and dogs, but also humans.
Ticks may be divided into hard and soft ticks, and are characterised by infesting one, two or three host animals. They attach themselves to a passing host animal and suck the blood or body fluids. Fully engorged female ticks drop from the host animal and lay large amounts of eggs (2000 to 3000) in a suitable crack in the floor or in any other protected site where the larvae hatch. These in turn seek a host animal, in order to suck blood from it. Larvae of ticks which only infest one host animal moult twice and thus become nymphs and finally adult ticks without leaving the host they have selected. Larvae of ticks which infest two or three host animals leave the animal after feeding on the blood, moult in the local environment and seek a second or third host as nymphs or as adult ticks, in order to suck its blood.
Ticks are responsible world-wide for the transmission and spread of many human and animal diseases. Because of their economic influence, the most important ticks are Boophilus, Rhipicephalus, Ixodes, Hyalomma, Amblyomma and Dermacentor. They are carriers of bacterial, viral, rickettsial and protozoal diseases and cause tick-paralysis and tick-toxicosis. Even a single tick can cause paralysis whereby its saliva penetrates into the host animal during ingestion. Diseases caused by ticks are usually transmitted by ticks, which infest several host animals. Such diseases, for example babesiosis, anaplasmosis, theileriasis and heart water disease, are responsible for the death or impairment of a large number of domestic and farm animals in the entire world. In many countries of temperate climate, Ixodide ticks transmit the agent of the chronically harmful Lyme""s disease from wild animals to humans. Apart from the transmission of disease, the ticks are responsible for great economic losses in livestock production. Losses are not confined to the death of the host animals, but also include damage to the pelts, loss of growth, a reduction in milk production and reduced value of the meat. Although the harmful effects of a tick infestation on animals have been known for years, and enormous progress has been made using tick-control programmes, until now no completely satisfactory methods of controlling or eliminating these parasites have been found, and in addition, ticks have often developed resistance to chemical active ingredients.
The infestation of fleas on domestic animals and pets likewise still represents for the owner a problem which has not been satisfactorily resolved or can only be resolved at considerable expense. As with ticks, fleas are not only troublesome, but are carriers of disease, and transmit various fungal diseases from host animal to host animal and to the animal keeper, particularly in moist, warm climatic areas, for example in the Mediterranean, in the southern part of USA, etc. Those at risk in particular are people with a weakened immune system or children whose immune system has not yet fully developed. Owing to their complex life cycle, none of the known methods for the control of fleas is completely satisfactory, especially as most known methods are basically directed towards the control of adult fleas in the pelt, and leave completely untouched the different juvenile stages of the fleas, which exist not only in the pelt of the animal, but also on the floor, in carpets, in the bedding of the animal, on chairs, in the garden and all other places with which the infested animal comes into contact. Flea treatment is usually expensive and has to be continued over long periods of time. Success usually depends on treating not only the infested animal, e.g. the dog or cat, but at the same time all the locations which the infested animal frequents.
Such a complicated procedure is unnecessary with the present compounds of formula (I( ), since a particular advantage of the compounds of formula (I) under discussion is that they are extremely effective and at the same time of very low toxicity both for the target parasites and for the warm-blooded animals. This is because their activity is based not on the death of the target parasite, but on the parrying defence thereof, before it attacks, sting, bites or in any other way harms the host organism. The presence of the compounds of formula (I) being discussed here appears to disturb the parasites in such a way that they suddenly leave the treated environment without biting or stinging, or even do not infest a treated host animal at all. What is striking is that the effect sets in when the parasite comes into contact with the active ingredient for a short time. After contact for a short time, the parasite avoids any further contact with the active ingredient. An additional advantage lies in the long-term action, e.g. compared with DEET (N,N-diethyl-m-toluamide), which although very effective, volatilizes rather rapidly and therefore has to be reapplied already after ca. 2 hours, and is thus not appropriate for the long-term treatment of animals. Usage of the present active ingredients is also pleasant because they are almost odourless.
Although the present active ingredients can of course be mixed with other substances having the same sphere of activity or with parasiticides or with other activity-improving substances to achieve further improved or longer-lasting action, and then applied, in contrast to many compounds of the prior art, this is totally unnecessary, as they already combine all the advantageous properties.
If the parasite is not only to be kept at bay, but also killed, of course this can be achieved by adding appropriate insecticides and/or acaricides. In practice, however, this is unnecessary in most cases.
The present active ingredients are preferably used in diluted form. Normally, they are brought to the final application form by using appropriate formulation excipients, and they then contain between 0.1 and 95% by weight, preferably 0.5 to 90% by weight of the active ingredient.
Since the active ingredients are in many instances applied to warm-blooded animals and of course come into contact with the skin, suitable formulation excipients are the excipients and administration forms that are known in cosmetics. They may be administered in the form of solutions, emulsions, ointments, creams, pastes, powders, sprays, etc.
For administration to farm animals or pets, such as cows, horses, asses, camels, dogs, cats, poultry, sheep, goats, etc., the so-called xe2x80x98pour-onxe2x80x99 or xe2x80x98spot-onxe2x80x99 formulations are especially suitable; these liquid or semi-liquid formulations have the advantage that they only have to be applied to a small area of the pelt or plumage, and, thanks to the proportion of spreading oils or other spreading additives, they disperse by themselves over the whole pelt or plumage, without having to do anything else, and become active over the whole area.
Of course, inanimate materials, for example clothing or dog and cat baskets, stables, carpets, curtains, living quarters, conservatories, etc. may be treated with said formulations and thus protected from parasite infestation.
To control cockroaches, their locus, usually cracks in the walls, furniture, etc., can be sprayed or powdered. Since cockroaches are extremely vigorous and it is almost impossible to drive them away completely, it is recommended that when using the present active ingredients, insecticides having activity against cockroaches are used additionally.
For application on humans, a pleasant-smelling essence, e.g. a perfume, can be added to make application more attractive.